Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor.

Details

Ressource 1Download: BIB_9D72B6BBBB7A.P001.pdf (478.15 [Ko])
State: Public
Version: author
Serval ID
serval:BIB_9D72B6BBBB7A
Type
Article: article from journal or magazin.
Collection
Publications
Title
Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor.
Journal
Molecular Therapy
Author(s)
Lanitis E., Poussin M., Hagemann I.S., Coukos G., Sandaltzopoulos R., Scholler N., Powell D.J.
ISSN
1525-0024 (Electronic)
ISSN-L
1525-0016
Publication state
Published
Issued date
2012
Volume
20
Number
3
Pages
633-643
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
Cancer regression by gene-modified T cells bearing a chimeric antigen receptor (CAR) exodomain of mouse origin can be limited by the induction of transgene immunogenicity resulting in poor persistence and function in vivo. The development of functionally-active CAR of human origin can address this issue. Here, we constructed and evaluated fully human anti-mesothelin CARs comprised of a human mesothelin-specific single-chain antibody variable fragment (P4 scFv) coupled to T cell signaling domains. Primary human T cells expressing P4 CAR specifically produced proinflammatory cytokines, degranulated and exerted potent cytolytic functions when cultured with mesothelin-expressing tumors in vitro. P4 CAR T cells also mediated bystander killing of mesothelin-negative cancer cells during coculture. CAR reactivity was not abrogated by soluble tumor-secreted or recombinant mesothelin protein even at supraphysiological levels. Importantly, adoptive transfer of P4 CAR-expressing T cells mediated the regression of large, established tumor in the presence of soluble mesothelin in a xenogenic model of human ovarian cancer. Thus, primary human T cells expressing fully human anti-mesothelin CAR efficiently kill mesothelin-expressing tumors in vitro and in vivo and have the potential to overcome the issue of transgene immunogenicity that may limit CAR T cell trials that utilize scFvs of mouse origin.
Keywords
Animals, Bystander Effect/immunology, Cell Line, Cytotoxicity, Immunologic, Epitopes/immunology, Female, GPI-Linked Proteins/immunology, GPI-Linked Proteins/metabolism, Gene Order, Genetic Vectors/genetics, Humans, Lentivirus/genetics, Mice, Ovarian Neoplasms/immunology, Ovarian Neoplasms/metabolism, Receptors, Antigen, T-Cell/genetics, Receptors, Antigen, T-Cell/immunology, Single-Chain Antibodies/genetics, Single-Chain Antibodies/immunology, T-Lymphocytes/immunology, T-Lymphocytes/metabolism, Transduction, Genetic, Xenograft Model Antitumor Assays
Pubmed
Web of science
Open Access
Yes
Create date
14/10/2014 11:43
Last modification date
20/08/2019 15:03
Usage data